Methodological quality and recommendations of hemophilia clinical practice guidelines: A scoping review

Abstract Background and Aims Hemophilia clinical practice guidelines (CPGs) play a vital role in guiding healthcare professionals' decisions. However, the quality and recommendations of CPGs for hemophilia may vary. This study aimed to assess the methodological quality of hemophilia CPGs published between 2017 and 2021 and compare their recommendations for prophylaxis using clotting factor concentrate. Methods We conducted a comprehensive search for relevant CPGs in PubMed, TripDatabase, Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) International Guidelines Database, Google Scholar, and Google. We used the AGREE‐II instrument to assess the methodological quality of each CPG and compared their recommendations for prophylaxis. Results Of the 11 CPGs that met the inclusion criteria, 5/11 were developed in upper‐middle‐income countries, and 6/11 used the GRADE methodology. The primary prophylaxis dose recommendations varied among the CPGs, with 4/11 recommending a low dose, 6/11 recommending an intermediate or high dose, and 1/11 not issuing a recommendation. However, only 2/11 CPGs provided justification for their recommendations on initiation and dose, and no economic evaluations were conducted to support these recommendations. Conclusion The quality of hemophilia CPGs is not optimal, with inconsistent recommendations for prophylaxis and a lack of justification for these recommendations. To ensure evidence‐based and trustworthy recommendations, there is a need for transparency and improvement in the decision‐making process of hemophilia CPGs.


| INTRODUCTION
Hemophilia is an inherited bleeding disorder caused by a deficiency of coagulation factor VIII (hemophilia A) or IX (hemophilia B), both X-linked recessive disorders. 1 Clinical manifestations relate to bleeding, bleeding sequelae, or complications of coagulation factor infusion. 2 It affects more than 1.2 million individuals worldwide, almost exclusively males. 3 Hemophilia A occurs in approximately 1 in 4000 to 5000 live male births, while Hemophilia B occurs in around 1 in 15,000 to 1 in 30,000 live male births. Severe disease is more common in hemophilia A. 4 The management of hemophilia is based on deficient clotting factor concentrates or by-pass agents when inhibitors are present. Indeed, factor concentrate is indicated as a prophylaxis measure to prevent long-term complications such as hemophilic arthropathy. 5 Clinical practice guidelines (CPGs) issue recommendations regarding which patients should receive primary prophylaxis with clotting factor concentrates and in what dose. However, these recommendations could be heterogeneous across countries due to differences in contexts and available resources and different methodologies used to reach evidence-based recommendations.
Thus, this study aims to perform a scoping review of the CPGs that address the management of hemophilia, assess their methodological quality, and compare their recommendations issued for prophylaxis with clotting factor concentrate.

| MATERIAL AND METHODS
We conducted a scoping review of CPGs for hemophilia, following the preferred reporting items for systematic reviews and metaanalyses guidelines for scoping reviews (PRISMA-ScR) to ensure the adequate reporting of this study. 6

| Eligibility criteria
We included CPGs that provided recommendations for the management of hemophilia, published between 2017 and 2021, and available in full text. We did not apply any language restrictions.

| Search strategy
During December 2021, we searched in five sources: Pubmed, TripDataBase, Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) International Guidelines Database, Google Scholar, and Google. The search strategies included terms such as "hemophilia," "guideline," and "recommendation" (Supporting Information: Table S1).

| CPGs selection and data extraction
Two researchers independently reviewed the documents to assess their eligibility (C. D. F. and D. G. G.). Discrepancies were resolved with a third researcher (A. T. R.).
Two authors performed data extraction independently (C. D. F. and L. P. C. for general data, and C. D. F. and D. G. G. for recommendations data) in Microsoft Excel spreadsheets. They extracted the following data for each CPG: general data (year, institution, country, income level of the country according to World Bank Data, 7

| Methodological quality assessment
We used the Appraisal of Guidelines for Research & Evaluation Instrument-II (AGREE-II) instrument to assess the methodological quality of the included CPGs. This instrument has 23 items in six domains (scope and purpose, stakeholder involvement, rigor of development, clarity and presentation, applicability, and editorial independence). Each CPG was rated by two authors (C. D. F. and L. P. C.). When the scores for a certain item had a difference greater than two points, we discussed the criteria of the item to reach a consensus. Then, we used the mean score for each item and followed the AGREE-II instrument guideline to calculate the score for each domain. 8 We used a cut-off of ≥ 60% to define an acceptable quality for each domain of the AGREE-II Instrument and the total score. We took this cut-off point from previous studies. 9-14

| Analyses
We used absolute and relative frequencies to present the results.
Also, we performed literal transcriptions or summarized the recommendations of interest.

| Ethics statement
This study does not involve human participants or animal subjects, and therefore, does not require institutional review board (IRB) approval.

| RESULTS
We found 678 records in database searching. After duplicates removal, we screened 670 records and finally included 11 hemophilia CPG that issued prophylaxis recommendations, published or updated between 2017 and 2021 ( Figure 1).

| Dose and criteria for dose selection
Considering the World Federation of Hemophilia (WFH) international guideline classification of doses, 5 we found that 4/11 CPGs 5,15,22,24 considered the possibility of starting prophylaxis from a low dose, 6/11 CPGs 16-21 considered starting prophylaxis from an intermediate or high dose, and 1/11 CPG 23 did not issue a recommendation on this regard (Table 3).  16,23 do not specify any criteria for dose selection (Table 3).

| Criteria for discontinuing prophylaxis
Regarding prophylaxis discontinuation, three CPGs 19,21,24 considered lifelong prophylaxis as a standard of care, 1/11 5 recommended lifelong prophylaxis but stated that continued monitoring should be performed in case of discontinuation, and the other 7/11 CPGs did not issue a recommendation regarding this topic (Table 3).  The decision-making regarding the dose of clotting factor concentrate for primary prophylaxis in hemophilia is complex and reveals several shortcomings. On the one hand, the lack of evidence (lack of randomized controlled trials that have compared different doses of different types of factors), and on the other hand, shortcomings in the decision-making process on the CPGs (no detailed information regarding the realization of the systematic reviews, benefits-harms balances, and cost assessments, to make the decisions). This is disturbing, given the high cost involved, the inequity that this may mean for low-income countries, and potential bias or conflicts of interest. resulted in the exclusion of some CPGs published entirely in other languages (with titles not translated into English). Second, we relied solely on the published information of each CPG and did not contact the authors for further details, although we adopted this approach to evaluate the information available to any reader of the CPGs.

| Conclusion
In conclusion, our findings indicate that the quality of hemophilia CPGs is not optimal, with inconsistent recommendations for prophylaxis and a lack of justification for these recommendations.
To ensure that future CPGs are evidence-based and trustworthy, there is a need to improve the transparency and rigor of the decisionmaking process in the development of hemophilia CPGs. This will allow healthcare professionals to better understand and evaluate the applicability of the recommendations in their specific contexts.

ACKNOWLEDGMENTS
This study was self-funded by the authors.

CONFLICT OF INTEREST STATEMENT
Carolina J. Delgado-Flores, David García-Gomero, and Alvaro Taype-Rondan participated in the elaboration of the clinical practice guideline for Hemophilia in EsSalud (Peru).

DATA AVAILABILITY STATEMENT
Data supporting the findings of this study are available in the supplementary material to this article.

TRANSPARENCY STATEMENT
The lead author Carolina J. Delgado-Flores affirms that this manuscript is an honest, accurate, and transparent account of the T A B L E 4 Recommendations regarding on-demand treatment with clotting factors in patients with Hemophilia A or B without inhibitors, issued by clinical practice guidelines.
No Author year (country) Recommendations on bleeding without immediate life-threatening

Recommendations on immediately life-threatening bleeding
CPGs from lower-middle-income countries 1 India-IAP (2018) Raise the plasma concentration of the factor to a level greater than or equal to 40-60 IU/dL in the availability of resources. In the absence of resources, consider 10-30 IU/dL. Does not mention the number of days.
Raise the plasma concentration of the factor to a level greater than or equal to 80-100 IU/dL in the availability of resources. In the absence of resources, consider 50-80 IU/dL. Does not mention the number of days. study being reported; that no important aspects of the study have